1. Field of the Disclosure
The present disclosure relates to a histaminase of vegetable origin to be used in the treatment of allergic and septic shock and of allergic asthma. The disclosure also regards the preparation of the histaminase for pharmaceutical use and the corresponding pharmaceutical compositions.
2. Discussion of the Background Art
Histaminase is an enzyme of the family of the amine oxidases. A method for its preparation is described in the U.S. Pat. No. 4,725,540, where histaminase is produced by micro-organisms and used for removing or degrading the histamine present in animal feed and in those foods that may be responsible for allergies, such as milk and its derivatives, so as to stem allergic phenomena affecting humans. Afterwards, histaminase is removed or in some way deactivated by the above-mentioned types of food.
Allergy is a complex phenomenon that may even affect internal organs, such as the heart and the lungs, causing bronchospasm, dyspnoea, asthma and shock. In particular, asthma is a chronic inflammatory state of the airways, in which numerous cells of the immune system co-operate, and which generates, in predisposed subjects, a constriction of the air flow at the bronchial level, with episodes of dyspnoea, breathlessness, thoracic oppression and coughing. The growing number of people in the world that suffer from asthma is a cause of great concern; today they amount to approximately 200 million (data issued by the World Health Organization). In 1997, 180,000 patients died from asthma (Humbert M., Le Scienze, 381, May 2000).
Histamine is the principal chemical mediator of the first phase of allergic reactions, and it is also known that many of the drugs currently available and used for the treatment of these clinical situations interact to some extent with this substance both by interfering with its release and by blocking its action at a receptor level.
Asthma and allergic shock have so far been treated using drugs, amongst which corticosteroids, anti-H1 anti-histamines, β2 stimulants and, in more serious forms, adrenaline. However, the above drugs present negative side effects.
In the treatment of allergic asthma and of allergic diseases in general, a basic therapy and an acute-attack therapy are known. In the immediate treatment of an attack of asthma, certainly by far the most effective drugs are the β2 agonists, in particular salbutamol. However, these drugs must be considered only symptomatic, in so far as they induce relaxation of smooth bronchial muscle without affecting at all the pathogenic mechanism of the allergic reaction. In addition, the effect of inhibition of the release of mediators of mast cells, which has been demonstrated for salbutamol in vitro and in vivo, is not, however, detectable in clinical use, given the acute conditions under which the drug is administered, as well as the brief duration of its action. Salbutamol and β2 agonists in general, notwithstanding the encouraging results obtained in in-vitro models and in experimental animals (for example, guinea pigs), have revealed, when administered to humans in the course of illness, the onset of important side effects, such as tachycardia, arrhythmias, tremors, cephalea, nausea, and vomiting (Ahrens R. C., Smith G. D., Albuterol: An adrenergic agent for use in the treatment of asthma; pharmacology, pharmacokinetics and clinical use. Pharmacotherapy, May-June 1984; 4 (3): 105-21).
Another drug indicated both in attacks of asthma and in anaphylactic shock on account of its marked β2-agonist action is adrenaline, a drug which is certainly effective and frequently a life-saver in emergency situations, but which also presents dangerous side effects (hyperglycaemia, dyspnoea, tachycardia, arrhythmias, cephalea, vomiting, and dizziness, up to the point of triggering attacks of angina in cardiac patients), which relegate its use only to life-threatening situations (Hoffman B. B., Lefkowitz R. J., Catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. In: Goodman and Gilman, The pharmacological basis of therapeutics, 9th edition. 199-248, 1996).
Ipratropium bromide, an M3 muscarine-receptor-antagonist drug for acetylcholine, has demonstrated a certain degree of efficacy as bronchodilatator and is considered a drug of second choice after β2 stimulants, compared to which it is less effective, but also better tolerated (Lovine R. R. Ed., Subtype of muscarine receptors. VI Life Sci. 1995, 56: 801, 1002).
The use of methyl xanthines via parenteral route, which are useful above all in the state of asthmatic illness, is extremely dangerous owing to the considerable systemic effects (risk of arrhythmias, panic attacks, convulsions), which limit their use to the more serious situations and involve the need for careful monitoring of the patient (Nasser S. S., Rees P. J., Theophylline. Current thoughts on the risks and benefits of its use in asthma. Drug Saf. January 1993; 8 (1): 12-8).
As far as basic treatment is concerned, the corticosteroids are the most effective drugs in the prevention of allergic reactions and present an action that is not only symptomatic, but also able to abolish some of the pathogenic mechanisms that underlie immuno-allergic phenomena. Their efficacy is beyond doubt both in attenuating the phenomenon in the acute phase and in the prevention of long-term relapse; however, in this case, the numerous side effects of these drugs inevitably emerge (hyperglycaemia, osteoporosis, suppression of the hypothalamus-pituitary-adrenal axis, dysphoria/depression, increase in weight, hydro-saline retention, gastro-duodenal ulcer, cataract, hypertension, immuno-suppression, suspension syndrome) (Lipworth B. J., Clinical pharmacology of corticosteroids in bronchial asthma. Pharmacol. Ther. 1993; 58 (2): 173-209).
H1 anti-histamines have for some time now represented one of the corner stones in the treatment of allergic phenomena. Their action is based upon the occupation of the H1 receptor (responsible for the effects of bronchoconstriction and cutaneous and mucous vasodilation), so that the histamine released by the immuno-phlogosis cells cannot express its action. Their acute effect is not particularly important, and they are in fact effective especially in the long-term prevention of attacks of asthma and of allergic cutaneous reactions. Their main side effects are at the level of the central nervous system (drowsiness) and of the gastro-intestinal apparatus (nausea, vomiting, epigastralgia, alterations of the alvus) (Holgate S. T., Antihistamines in the treatment of asthma. Clin. Rev. Allergy Spring 1994; 12 (1): 65-78).
The chromones (disodium chromoglycate, Nedocromil sodium) are used in the prevention of asthma attacks and above all of allergic rhinitis on account of their properties for stabilizing the mast-cell membrane; they do not present particular side effects (rare cases of sensitization, cephalea and nausea are reported) but have a modest efficacy, even in the mild forms of asthma (Brogden R. N., Sorkin E. M., Nedocromil sodium. An updated review of its pharmacological properties and therapeutic efficacy in asthma. Drugs, May 1993; 45 (5): 693-715).
Leukotriene-receptor antagonists (Zafirlukast, Montelukast) have recently proved useful for reducing the use of corticosteroids in the prevention of asthma attacks in mild-to-moderate forms; however, their action starts to appear only after 2 weeks of treatment (Diamant Z., Sampson A. P., Anti-leukotriene therapy for asthma. In: Anti-inflammatory drugs in asthma. Sampson & Church Eds., Birkäuser, Basel, 1999).
From the foregoing it emerges how, notwithstanding the constant endeavour aimed at countering allergic phenomena, given their enormous negative impact on the world population, so far no effective means have come available. The need was thus felt for the development of an effective drug and one exempt from side effects for the treatment of allergies in general, and of asthma and allergic and septic shock in particular.